Disclosures: Fredrick M Wigley, MD Grant/Research/Clinical Trial Support: United Therapeutics [Raynaud's Phenomenon (treprostinil)]. John S Axford, DSc, MD, FRCP, FRCPCH Nothing to disclose. Monica Ramirez Curtis, MD, MPH Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — The Raynaud phenomenon (RP) is an exaggerated vascular response to cold temperature or to emotional stress, which is manifested clinically by sharply demarcated color changes of the skin of the digits. Treatment includes patient education and general measures taken by the patient to prevent and treat attacks, and may include pharmacologic interventions and surgical sympathetic blockade to prevent and treat digital ischemia.
The treatment of RP in patients resistant to initial therapy is reviewed here. The initial therapy of RP, including general measures, the use of calcium channel blockers (CCBs), and behavioral interventions, as well as the pathogenesis, clinical manifestations, and diagnosis of RP, is presented separately. (See "Initial treatment of the Raynaud phenomenon" and "Pathogenesis of the Raynaud phenomenon" and "Clinical manifestations and diagnosis of the Raynaud phenomenon".)
PRIMARY AND SECONDARY RP — The Raynaud phenomenon (RP) is considered primary if the symptoms occur alone without any associated disorder; secondary RP refers to the presence of the disorder in association with a related illness, such as systemic lupus erythematosus (SLE) or systemic sclerosis (scleroderma). Primary RP is sometimes also referred to as idiopathic RP or Raynaud disease. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon".)
Patients with primary RP are generally not significantly disabled by the attacks, although the quality of life may be affected by the need for cold avoidance and by the lack of normal finger sensation. An initially conservative, nonpharmacologic approach is therefore most important for these patients, although pharmacologic therapy may ultimately be necessary. By comparison, patients with secondary RP are more likely to have severe attacks, and disease management is more likely to be based upon pharmacologic agents, while continuing nonpharmacologic measures.
GOALS AND OVERVIEW OF THERAPY — The goals of therapy are to improve quality of life and to prevent ischemic tissue injury. At least a moderate reduction in the intensity of attacks and the prevention of digital ulcers or tissue injury are achievable in most patients. However, abolishing cold sensitivity and eliminating all Raynaud events is not likely with available treatment options, particularly in patients with secondary Raynaud phenomenon (RP), due to the complexity and sensitivity of the regulation of thermoregulatory vessels in the skin. (See "Pathogenesis of the Raynaud phenomenon".)
The efficacy of the treatment depends upon the severity of disease and upon the presence or absence of an underlying disorder; this is particularly important in patients with an underlying systemic rheumatic disease related to systemic sclerosis (scleroderma), as such patients can have a structural component to their vascular disease in addition to the vasospastic component seen in all patients with RP.
Initial therapy — The initial treatment of patients with the RP is described in detail elsewhere. (See "Initial treatment of the Raynaud phenomenon".)
Briefly, such treatment includes:
●Patient education and general nonpharmacologic measures in all patients for the prevention and treatment of RP. General measures include (see "Initial treatment of the Raynaud phenomenon", section on 'Patient education' and "Initial treatment of the Raynaud phenomenon", section on 'General measures'):
•Avoiding cold exposure
•Maintaining whole body and digital warmth
•Avoiding sympathomimetic medications and emotional stress
●Treatment with calcium channel blockers (CCBs) in patients who do not respond adequately to general nonpharmacologic measures (see "Initial treatment of the Raynaud phenomenon", section on 'General measures insufficient' and "Initial treatment of the Raynaud phenomenon", section on 'Calcium channel blockers')
●Behavioral interventions in selected patients (see "Initial treatment of the Raynaud phenomenon", section on 'Behavioral therapy')
Patients resistant to initial therapy — In patients with RP who do not respond adequately to initial therapies, further steps include:
●The addition or substitution of other pharmacologic agents, such as topical nitrates or phosphodiesterase 5 inhibitors, if CCBs are insufficient (see 'Resistant to initial therapies' below and 'Combination of a CCB with other vasodilators' below)
●Treatment with an intravenous (IV) prostanoid in patients with threatened or established digital ischemia that has not responded to oral or topical vasodilators (see 'Severe symptoms despite oral and topical agents' below and 'Efficacy of parenteral prostaglandins and analogues' below)
●Endothelin-1 receptor antagonist treatment in patients with digital ischemia and recurrent digital ulcers secondary to systemic sclerosis (scleroderma) (see 'Recurrent digital ulcers in scleroderma' below)
●Chemical sympathectomy, with a digital or regional block, used in patients with critical digital ischemia as a temporary measure prior to initiation of vasodilator therapy including IV prostanoids (see 'Chemical sympathectomy' below)
●Additional therapies, which may include anticoagulation, analgesics, antibiotics, and surgical debridement as clinically indicated (see 'Anticoagulation and antithrombotic therapy' below)
Expected duration of benefit — The duration of benefit from drug intervention in RP has not been formally studied. Most reported clinical trials are short-term, typically four to six weeks in duration. In our experience, there is sustained benefit from treatment with a CCB. This impression is based upon the consistent occurrence of relapses of severe Raynaud events if a CCB is discontinued. However, there are little objective data to define the duration of benefit of single or combination drug therapy.
Similarly, careful long-term studies of the outcome following surgical intervention or injection therapy (eg, with botulinum toxin A) are not adequate to provide guidance. Our impression is that the RP recurs following surgical digital sympathectomy, but is usually not as severe as prior to surgery.
Each patient needs to be evaluated periodically for the need for a particular intervention. It is important to take into account the risk of the intervention, the clinical evidence for its effectiveness, and the need for continued therapy at the time of the evaluation, balancing the risks of therapy and the level of severity of the RP.
RESISTANT TO INITIAL THERAPIES — In patients resistant to initial therapies, including general nonpharmacologic measures and maximum tolerated doses of calcium channel blockers (CCBs) known to be effective for the treatment of Raynaud phenomenon (RP), we use the following measures:
●We review and reinforce the importance of continuing the general nonpharmacologic measures for prevention and treatment. (See "Initial treatment of the Raynaud phenomenon", section on 'Patient education' and "Initial treatment of the Raynaud phenomenon", section on 'General measures'.)
●We revisit the underlying cause for the RP to readdress reversible causes or treatable aggravating or comorbid conditions.
●We add or substitute one of the following:
Combination of a CCB with other vasodilators — In patients who do not respond adequately to a CCB alone, we suggest the addition of either a PDE inhibitor (eg, sildenafil) or another vasodilator. In patients in whom a PDE inhibitor is not available, effective, or well-tolerated, we suggest the use of topical nitrates. (See 'Phosphodiesterase type 5 inhibitors' below and 'Topical nitrates' below.)
Both classes of vasodilators have shown benefit in several randomized trials in patients with primary or secondary RP compared with placebo, but results have been mixed. Combination therapy of a CCB and another vasodilator has not been adequately evaluated in randomized trials, but is increasingly being used in practice in difficult situations such as RP related to scleroderma with associated digital ulceration.
Phosphodiesterase type 5 inhibitors — In patients who have obtained some but inadequate benefit from a CCB and who tolerate that therapy, we suggest the addition of a PDE type 5 inhibitor and continue the CCB. In patients who do not benefit from the CCB, we either add a PDE inhibitor or try the PDE inhibitor as an alternative, depending upon the ability to tolerate the medications, if critical ischemia is not present. (See 'Severe symptoms despite oral and topical agents' below.)
Based upon the available evidence and our clinical experience, we initiate therapy at a low dose (eg, sildenafil 20 mg once or twice daily) and increase the dose to 20 mg three times daily if no benefit is achieved. This dose is similar to that used in patients with pulmonary hypertension. A four- to six-week trial should be adequate to determine whether the combination is of benefit. (See "Pulmonary vascular disease in systemic sclerosis (scleroderma): Treatment", section on 'Phosphodiesterase type 5 inhibitors'.)
Care must be taken to fully assess cardiopulmonary status (eg, for pulmonary hypertension) before starting combined vasodilation therapy. Systemic blood pressure measurements should be followed serially. When possible, we advise patients to obtain a blood pressure (BP) cuff and to monitor their BP daily at first until dosing is stable and then weekly thereafter, as well as when symptoms of hypotension occur.
A PDE inhibitor should not be used together with topical nitrates due to the increased risk of hypotension. Other adverse effects that may occur include peripheral edema, palpitations, tachycardia, hearing loss, and visual disturbances.
The increasing use of these medications in efforts to improve peripheral and pulmonary circulation in several disorders is discussed in separately. (See "Pulmonary vascular disease in systemic sclerosis (scleroderma): Treatment", section on 'Phosphodiesterase type 5 inhibitors' and "Treatment of idiopathic pulmonary fibrosis", section on 'Phosphodiesterase inhibitors'.)
Efficacy of PDE inhibition — The efficacy of sildenafil, tadalafil, and vardenafil was best examined in a meta-analysis of six randomized controlled trials that included 244 patients with secondary RP . There was a modest but significant benefit of PDE inhibitors on Raynaud’s Condition Score (RCS), as well as on the frequency and duration of RP attacks . PDE inhibitors reduced the frequency of RP attacks by approximately 0.5/day compared with placebo, which is comparable to the reduction reported in another meta-analysis assessing the efficacy of CCBs in systemic sclerosis (SSc)-related RP (0.6/day) . The RCS represents the level of difficulty experienced by the patient each day that is attributed to RP, and is assessed using a visual analog scale. Although the improvement in the RCS was significant, it was not a clinically meaningful difference  (see "Initial treatment of the Raynaud phenomenon", section on 'Assessment of the response to therapy') Additional well-designed trials involving more patients are needed to better assess the role and optimal dosing of sildenafil, tadalafil, vardenafil, and other PDE inhibitors in primary and secondary RP.
Topical nitrates — In patients with an inadequate response to a CCB and for whom a phosphodiesterase inhibitor is not available, effective, or well-tolerated, we suggest the addition of topical NTG, based upon benefit of various forms of topic nitrates in several randomized trials and in our clinical experience [4-8]. Nitrates have been used for the treatment of primary and secondary RP, with different methods of delivery including sustained-release transdermal patches, creams, gels, and ointments.
We have found the topical nitrates to be more useful for patients with a single or small number of more severely affected digits and for short-term (days to weeks) use, compared with patients with more diffuse involvement and with the need for chronic (months to years) use. However, the efficacy of topical nitrates and duration of benefit are not well-defined, and significant side effects such as headache may occur with most forms of these agents.
Topical NTG (eg, 0.5 inches [about 1.3 cm] of 2 percent ointment, approximately 15 mg/inch [38 mg/cm]) should be applied to a single more severely affected or ischemic digit for 6 to 12 hours while continuing use of the CCB. The dose of topical NTG may vary depending upon the preparation and should be adjusted with close monitoring of tolerance and the clinical response. The NTG 2 percent ointment can be titrated as needed up to a full 2 inches (about 5.1 cm) every four to six hours with a 12-hour nitrate-free period. However, the higher dose is often not well-tolerated, and patients stop usage. The dose may be divided between several digits, although absorption with most preparations results in systemic effects. Preparations in development that are not available commercially may have reduced systemic absorption and fewer systemic adverse effects [3,5].
Potential side effects include headache, flushing, lightheadedness, decreased blood pressure, tachycardia, and aggravation of gastroesophageal reflux.
In patients with low blood pressure, dehydration, acute or chronic heart failure, pulmonary hypertension, or ongoing use of a PDE inhibitor, topical nitrates should generally be avoided; they should be used with great caution and in low dose if essential for treatment for such patients.
Several small observational studies and randomized trials of different topic nitrates have provided evidence for benefit in patients with RP [4-8]. The efficacy and tolerability of topical nitrates were evaluated in a randomized trial involving 219 patients with primary or secondary RP, in which application of a novel formulation of topical NTG provided benefit without significant adverse effects . Topical NTG, MQX-503 (as a 0.5 gram aliquot of 0.9 percent gel), was applied before or within five minutes after the onset of an attack of RP, resulting in a statistically significant greater reduction in the RCS, compared with use of a matching placebo gel (14.3 versus 1.3 percent). This degree of improvement in the RCS is at the level reported to meet a minimally important difference . The frequency and duration of attacks and of side effects, including headache and dizziness, did not differ between groups. This preparation is not available commercially.
Other alternatives to CCBs — In patients who do not reach the therapeutic goal or who are unable to tolerate a CCB, a PDE type-5 inhibitor, or a topical nitrate, alone or in combination, we use one of the other oral agents for which there is some, although very limited, evidence of benefit. Most studies of these agents do not provide solid evidence of efficacy due to small sample sizes, limited duration of study, or a lack of control data [8-12]. These agents include:
●Prazosin, an alpha-1-adrenergic receptor antagonist – In two small randomized trials, prazosin has been reported to improve RP [13,14]. As an example, a blinded crossover study of 14 patients evaluated the effect of prazosin among patients with primary and secondary RP . Eight of nine patients with systemic lupus erythematosus (SLE), mixed connective tissue disease, or primary RP were clinically improved with active therapy. Only one of five patients with scleroderma reported improvement with prazosin. Patients will typically eventually become refractory to this agent after prolonged usage, in our experience.
Other sympatholytic drugs in addition to prazosin have been used in RP including methyldopa and reserpine (which has been given intra-arterially) [13-22]. However, none of these agents is a specific inhibitor of the alpha-2C-adrenergic receptor that is thought to be the major pathway through which cold-induced digital artery vasoconstriction is triggered. A laboratory-based study using a specific alpha-2C adrenergic receptor antagonist demonstrated improvement in cold-induced skin temperature, suggesting that similar agents may be helpful in the treatment of RP, but a specific alpha-2C agent is not available .
●Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) – Limited data suggest that SSRIs, primarily fluoxetine, may be of benefit for RP [24,25]. The effects over six weeks of treatment with fluoxetine (20 mg daily) were compared with those of nifedipine (40 mg daily) in an open-label crossover study involving 53 patients with primary and secondary RP; use of fluoxetine resulted in statistically significant reductions in the severity and frequency of attacks (by approximately 50 and 40 percent, respectively), but the decreases in severity and frequency of attacks with nifedipine (by approximately 25 to 30 percent and 15 to 20 percent, respectively) did not achieve statistical significance .
●Losartan, an angiotensin II receptor blocker – Losartan (50 mg/day) resulted in a greater reduction in the severity and frequency of attacks in patients with primary RP and secondary (scleroderma-related) RP in a 12-week study in comparison with nifedipine (40 mg/day) .
●Angiotensin-converting enzyme inhibitors – There is little evidence to suggest that angiotensin-converting enzyme (ACE) inhibitors are effective for RP. Despite an open-label study that suggested some benefit from use of captopril in patients with primary (but not secondary) RP, a subsequent randomized trial involving 210 patients with secondary RP did not support the use of an ACE inhibitor for this indication [27,28]. The trial found no evidence of benefit for quinapril, an ACE inhibitor, in the incidence of digital ulcers or in the frequency or severity of attacks of RP .
Several additional medications, which are used but for which there are very limited data to define clinical utility, include:
●Statins, which have been evaluated in an open-label study and a randomized trial for the treatment of scleroderma vascular disease [30,31]. Preliminary studies using atorvastatin demonstrated reduced severity and frequency of Raynaud events, as well as reduction of ulcer formation, compared with placebo in patients with scleroderma. More studies are needed to define the role of statins in secondary Raynaud phenomenon. We limit the use of statins for RP to patients with scleroderma and recurrent digital ulcerations not responding to standard therapies and add it to other ongoing therapies. The rationale for the use of these agents includes their pleiotropic effects, which may help protect the vasculature or prevent vascular events including, in theory, their ability to inhibit the rho-kinase pathway, which regulates alpha-2C adrenergic receptor expression .
●Antioxidant agents, such as zinc gluconate (50 to 150 mg/day), which have also been utilized based upon the rationale that they may reduce tissue damage that may occur during ischemia-reperfusion from superoxide production [33-35]. In one study, intravenous (IV) N-acetylcysteine reduced the frequency and severity of RP attacks compared with baseline and, in another uncontrolled study, reduced digital ulcers and severity of RP in scleroderma patients [36,37]. Probucol, a synthetic antioxidant, improved RP compared with a control group .
●Ginkgo biloba, an herbal medication that we do not use because the preponderance of evidence has not shown it to be beneficial [39,40].
A number of other agents have been studied but failed to show adequate benefit or acceptable levels of safety compared with other available medications, including ketanserin, L-arginine, calcitonin gene-related peptide, and a thromboxane A2 inhibitor [41-44]. Other such agents include direct vasodilators, such as nitroprusside; hydralazine; papaverine; minoxidil; niacin; and topical agents, including nitric-oxide (via a generating system), hexyl nicotinate, and ethyl nicotinate [4,45]. Sarpogrelate hydrochloride, a 5-hydroxytryptamine 2A serotonin receptor (5-HT2A) inhibitor available in Japan, has been reported to improve RP and to reduce digital ulcers [46-48].
SEVERE SYMPTOMS DESPITE ORAL AND TOPICAL AGENTS — In patients with threatened or established digital ischemia that has not responded to optimal therapy with oral or topical vasodilators, we suggest treatment with intravenous (IV) infusions of a prostaglandin (PG), preferably a prostacyclin (PGI2) analogue such as iloprost, epoprostenol, or treprostinil, depending upon availability (which varies between countries). The duration of such therapy is determined by the clinical outcome. Such patients may have severe symptoms that have a markedly adverse effect upon quality of life, or they may have digital ulcers or macrovascular events associated with Raynaud phenomenon (RP) that threaten digital loss.
In countries where endothelin-1 antagonists have received regulatory approval for use in systemic sclerosis (scleroderma), use of these agents (eg, bosentan) for the prevention of new digital ulcers may precede use of IV PG in patients with scleroderma who do not require more urgent intervention. (See 'Recurrent digital ulcers in scleroderma' below.)
Some patients with severe symptoms of RP but without digital ulcers may prefer to avoid use of IV therapy. In some countries, such as the US, cost may be prohibitive for some patients due to lack of insurance coverage.
IV PG therapy is often administered in an inpatient setting, but hospitalization may not be required in uncomplicated, stable patients with an established diagnosis if an outpatient infusion center with monitoring is available. The latter approach is often utilized for administering iloprost outside of the US.
A careful review of ongoing vasodilator therapy should be undertaken prior to using IV PG to assure that the use of these first-line agents has been optimized, given the substantial inconvenience and potential cost of IV PG therapies. (See "Initial treatment of the Raynaud phenomenon", section on 'Calcium channel blockers' and 'Resistant to initial therapies' above and 'Combination of a CCB with other vasodilators' above.)
The use of parenteral PG analogues for patients with severe digital ischemia is supported by multiple randomized trials and by systematic reviews and meta-analyses of such trials [11,49]. The mechanisms of action may include potent vasodilatory effects, inhibition of platelet aggregation, and improvement of abnormal vascular reactivity. Parenteral (typically IV) administration of several PG and PG analogues has been studied in the setting of severe digital ischemia. The use of oral PG analogues has been studied in primary and secondary RP, but there is insufficient evidence to support their use in clinical practice. (See 'Efficacy of parenteral prostaglandins and analogues' below and 'Oral prostaglandins and analogs' below.)
The options include:
●Treprostinil, which may be given by subcutaneous injection or intravenously . However, in patients receiving the medication by subcutaneous injection, local pain at the injection site limits use in many patients, and its use in patients with severe symptoms of RP or critical ischemia by either the subcutaneous or IV route has not been reported.
●Alprostadil (PGE1), an alternative that has been administered at a dose of 6 to 10 ng/kg per minute through a central IV line . However, PGE1 has not been proven effective for treating RP [54-56].
Initial randomized trials with iloprost used a peripheral vein infusion at maximum rate of 2 ng/kg/minute for six hours each session for five days; the treatment group experienced significantly greater benefit compared with the placebo group over a nine-week follow-up . Based upon this experience, several weeks of improvement would be expected with this approach, justifying intermittent treatment during a problem period such as winter months. In an acute ischemic crisis, a rapid reversal of symptoms usually occurs. Side effects of therapy are usually reversible with a reduction in dose. The dose of IV PG should be adjusted to the level that is tolerated. (See 'Efficacy of parenteral prostaglandins and analogues' below.)
Calcium channel blockers (CCBs) and other agents, such as topical nitrates or phosphodiesterase inhibitors, are continued in patients receiving a treatment course of IV PG (between infusions) but are generally not administered when patients are also receiving infusions.
Efficacy of parenteral prostaglandins and analogues — Multiple studies have examined the efficacy of treatment of severe refractory RP and ischemic digital ulcers with preparations of iloprost (a PGI2 analog) [50,57,58], epoprostenol (a PGI2 analog) [51,52], and PGE1 [54,55,59].
Iloprost — Iloprost is an analog of PGI2. Evidence of benefit for this agent in severe digital ischemia includes randomized trials and other studies that have employed varying doses and schedules for drug administration.
A systematic review and meta-analysis involving 332 patients in seven randomized trials showed benefit in patients with secondary RP associated with scleroderma, with evidence for decreasing the severity and frequency of acute attacks and for preventing or healing digital ulcers . Dosing regimens in the trials varied. The effect was prolonged beyond the period of the infusion, and limited data suggested that the IV preparation was more effective than oral iloprost.
The range of findings and approaches are illustrated by the following:
●A randomized trial involving 131 patients with secondary RP associated with scleroderma, which showed the efficacy of iloprost given intravenously (0.5 to 2 ng/kg per minute for six hours on five successive days) compared with placebo . Iloprost use resulted in short-term palliation of severe RP. The mean weekly attack rate and the Raynaud severity score both decreased in the patients treated with iloprost compared with those receiving placebo (39 and 35 percent versus 22 and 20 percent, respectively).
Adverse events were seen in significantly more patients treated with iloprost compared with those receiving placebo (92 versus 57 percent). The most common side effects included headache (54 versus 21 percent), flushing (32 versus 6 percent), and nausea (29 versus 11 percent). Jaw pain, diarrhea, vomiting, injection site reactions, and myalgia were also common (5 to 15 percent versus 0 to 2 percent). The side effects were reversed by decreasing the dose of the iloprost and the rate of infusion. Hypotension and rashes may also occur. Withdrawal from the trial, usually for lack of benefit, was similar in the two groups (13 percent).
●A study that found short-term infusions of IV iloprost (for eight hours/day on three consecutive days, with a repeat infusion for one day on week eight) comparably effective to oral nifedipine (up to 60 mg/day as tolerated for 16 weeks) in secondary RP associated with scleroderma 
●The use of iloprost in 30 patients with scleroderma with maintenance infusions every three weeks for a median of three years following an initial cycle of infusions over five days . Healing of digital ulcers and a subjective decrease RP were reported in this long-term uncontrolled study.
Other prostacyclins — PGI2 is also available for clinical use in some countries as epoprostenol (a PGI2 analogue), which has been most widely used for the treatment of idiopathic pulmonary hypertension and which has been used for pulmonary hypertension associated with scleroderma. Another PGI2 analogue, treprostinil, has been evaluated primarily as a subcutaneous injection but can be given via IV infusion. Inhaled PGI2 (iloprost and treprostinil) is also available, but little experience is available to guide usage for RP . (See "Treatment of pulmonary hypertension in adults".)
Evidence supporting use in patients with severe RP and digital ischemia includes:
●Small observational studies and randomized trials of PGI2 in RP, which showed benefit following IV infusion at the rate of 7.5 to 10 ng/kg per minute for three five-hour periods [51,52]. The short-term benefit is similar to that reported with iloprost in our experience.
●Findings in a randomized trial of epoprostenol for pulmonary hypertension associated with scleroderma and related disorders, which showed a favorable but statistically nonsignificant difference in the severity of RP and fewer new digital ulcers in the epoprostenol-treated patients 
●Improvement in digital ischemia and ulceration in patients with scleroderma who received subcutaneous infusions of a PGI2 analog (treprostinil) [53,63]. Unfortunately, many of the patients studied were unable to tolerate and continue receiving the medication due to severe injection site pain. Treprostinil can also be given intravenously.
Oral prostaglandins and analogs — Preparations of oral PG and analogues are available for study in Japan, Europe, and the United States, but further study, including randomized trials, will be required to establish the role of oral PG in the management of severe RP. Mixed results have been obtained in studies evaluating their efficacy in RP.
●One study found that misoprostol (an oral preparation of PGE1) did not reverse cold-induced vasospasm ; however, another report found that limaprost (another oral PGEI analogue) increased peak digital blood velocity in patients with systemic lupus erythematosus (SLE) and mixed connective disease (but not scleroderma) .
●Cicaprost, a synthetic PGI2 analogue, reduced the severity of the Raynaud phenomenon in one study .
●Oral iloprost was studied in two placebo-controlled trials of patients with scleroderma [69,70]. Oral iloprost was no better than placebo for the management of RP. Use of inhaled iloprost has also been reported .
Botulinum toxin A — Intra-digital and palmar injection of botulinum toxin A is reported to improve digital blood flow and reduce severity of RP [72-74] (see 'Chemical sympathectomy' below). However, the evidence is based on uncontrolled case series and the exact role of botulinum toxin in the treatment of RP has yet to be defined. We have reserved its use for patients with severe RP who are not responding to or tolerating oral vasodilator therapy.
RECURRENT DIGITAL ULCERS IN SCLERODERMA — In patients with recurrent digital ulcers associated with systemic sclerosis (scleroderma) or related disorders and with continued or recurrent symptoms despite use of other therapies, including calcium channel blockers (CCBs) plus other agents and intravenous (IV) prostaglandins (PG), we suggest the use of bosentan, an orally administered inhibitor of the potent vasoconstrictor endothelin-1, based upon several randomized trials involving patients with scleroderma; these trials demonstrated a reduced frequency of new digital ulcers in such patients [75,76]. Bosentan has been used primarily for the treatment of pulmonary hypertension. (See "Pulmonary vascular disease in systemic sclerosis (scleroderma): Treatment", section on 'Endothelin-1 receptor antagonists' and "Treatment of pulmonary hypertension in adults", section on 'Bosentan'.)
There is inadequate evidence to indicate whether bosentan should be used prior to IV PG to prevent recurrent digital ulcers in patients with scleroderma, although it has received regulatory approval in Europe for this indication. The choice of agents in this setting should be individualized. Some experts have greater experience with IV iloprost, and there is greater risk of hepatotoxicity with bosentan, which requires close monitoring and which may be a particular concern in some patients. Clinician preference and experience with each treatment option, as well as patient preference regarding route of administration, frequency of outpatient monitoring, comorbidities, regulatory factors, and cost, may affect treatment choice.
Treatment with bosentan is initiated at a dose of 62.5 mg twice daily for four weeks. The dose should be increased to 125 mg twice daily in patients who do not benefit from the initial dose. Liver function tests should be obtained monthly in patients receiving the medication to monitor for hepatic toxicity. The following trials illustrate the clinical benefits and limitations of bosentan:
●A randomized trial to directly examine its effect on recurrent digital ulcers in 122 patients with scleroderma noted a 50 percent reduction in new ulcers among those who had ulceration at baseline; however, there were no reduction in frequency or intensity of attacks of Raynaud phenomenon (RP) and no improvement in ulcer healing in patients with digital ulcers at baseline .
●A subsequent trial in 188 patients with scleroderma with digital ulcers at trial entry found a statistically significant 30 percent reduction in new digital ulcers compared with placebo (1.9 versus 2.7) but also observed no differences in the healing rate of the cardinal ulcer . Peripheral edema and elevated aminotransferases were associated with bosentan use. Further studies are needed to better define the role of bosentan or other endothelin antagonists in the treatment of secondary RP.
Commonly reported side effects are headache, flushing, edema (18 percent), hypotension, liver enzyme elevation (12 percent), and fatigue. Less common but more serious reactions include liver failure, bone marrow suppression, and angioedema. In the clinical trials, about 15 percent of patients discontinued therapy due to side effects. Selective endothelin-1 antagonists that are less toxic to the liver may have the potential of being helpful, but evidence regarding their use in this population is not available
Evidence for the use of statins in scleroderma patients with recurrent digital ulcers is limited [30-32]; however, a statin such as atorvastatin can be used as an alternative to bosentan if the latter agent is unavailable, is ineffective, or is poorly tolerated.
DIGITAL ULCERATION WITH CRITICAL ISCHEMIA
Approach to treatment — Early intervention is very important in patients who develop digital ulcers with deeper tissue critical ischemia (eg, threatening loss of a portion of a digit); we take the following approach:
●Patients with a demarcated ischemic digit secondary to larger vessel compromise should be hospitalized, kept warm and quiet, and fully evaluated for a secondary reversible process that is causing or aggravating the crisis. This includes a careful evaluation for correctable macrovascular disease, vasculitis, or an embolic or hypercoagulable state. (See "Noninvasive diagnosis of arterial disease" and "Classification of and approach to the vasculitides in adults".)
●Pain due to severe ischemia may be intense, and adequate pain control may require the use of narcotic analgesics. (See "Overview of the treatment of chronic pain" and "Pain control in the critically ill adult patient".)
●In patients who are not receiving medical therapy for Raynaud phenomenon (RP), we recommend starting a short-acting calcium channel blocker (CCB), because of the urgency of intervention, as a vasodilator. We also suggest low-dose aspirin (75 to 81 mg/day) as a component of the initial therapy in patients with scleroderma and acute digital ischemia, if there is no contraindication. However, there are inadequate studies to define the optimal approach to antiplatelet therapy in such patients. (See 'Severe symptoms despite oral and topical agents' above and 'Anticoagulation and antithrombotic therapy' below.)
●Based upon clinical experience, we suggest temporary chemical sympathectomy when oral and/or topical vasodilatory therapy does not quickly result in improvement in digital blood flow. This technique may provide relief while efforts are underway to obtain and prepare for administration of prostaglandins. If intravenous (IV) prostaglandins (PG) are readily available, such treatment is preferred to chemical or surgical sympathectomy. However, in some patients, chemical sympathectomy can lead to a reversal of symptoms that may be sustained, and PG infusions may not be required. (See 'Chemical sympathectomy' below.)
●We suggest treatment with IV PG, as described for patients with severe symptoms of RP. An alternative preferred by some experts, especially if there is a lack of experience or of availability of IV PG, is to proceed to surgical sympathectomy of the digit or hand rather than the IV therapy. (See 'Severe symptoms despite oral and topical agents' above and 'Efficacy of parenteral prostaglandins and analogues' above and 'Sympathectomy' below.)
●Early intervention with thrombolytic therapy may be used in selected patients with a newly defined thrombotic or embolic event [78,79]. (See 'Anticoagulation and antithrombotic therapy' below and "Overview of acute arterial occlusion of the extremities (acute limb ischemia)".)
●We advise the addition of either unfractionated or low-molecular-weight heparin (LMWH) for a period of 24 to 72 hours if critical digital ischemia develops during vasodilator therapy and/or if the new onset of arterial occlusion is thought to be secondary to acute thrombosis or embolization. (See 'Anticoagulation and antithrombotic therapy' below.)
Sympathectomy — In patients with digital ulceration with critical ischemia, when oral and/or topical vasodilatory therapy does not quickly result in improvement in digital blood flow and when IV PG are not readily available, we suggest, based upon clinical experience, that temporary chemical sympathectomy be performed with a digital or regional block. Chemical sympathectomy has not been systematically evaluated in clinical trials. We do not perform temporary cervical or lumbar sympathectomy because of the lack of evidence of lasting benefit. In addition, there is no evidence that a temporary sympathectomy will predict the degree of benefit of a permanent sympathectomy. Patients may also undergo either proximal or distal surgical sympathectomy. (See 'Chemical sympathectomy' below and 'Cervical sympathectomy' below and 'Localized surgical digital sympathectomy' below.)
Chemical sympathectomy — A temporary local chemical sympathectomy that can reverse vasoconstriction involves a digital or regional (eg, wrist) block with local infiltration of lidocaine or bupivacaine (without epinephrine) [80,81]; this procedure also relieves pain. Intra-digital and palmar botulinum toxin A has also been used for chemical sympathectomy.
Temporary cervical or lumbar sympathectomy is rarely used unless other approaches have failed, because it does not have long-lasting benefit; however, sometimes it is temporarily effective in reversing acute vasospasm [82,83]. Continuing medical therapy will hopefully maintain the improvement over time in patients treated with this approach.
In several studies of small numbers of patients with primary and secondary RP, intra-digital and palmar injection of botulinum toxin A appears to inhibit vasoconstriction, relieve clinical symptoms, improve skin blood flow, and be associated with the healing of digital ulcers [72,84-89]. The use of botulinum toxic is limited by cost, the need for repetitive treatments, the lack of robust clinical trials, and the absence of well-defined long-term follow-up.
Cervical sympathectomy — Several reports have suggested that cervical sympathectomy is helpful in primary RP but not in secondary forms [90-93]. However, these studies are generally more than 30 years old, are either individual cases or surveys, and have included patients with various causes of RP or different types of peripheral vascular disease. It is, therefore, difficult to draw any firm conclusion concerning the benefit of sympathectomy in RP. This procedure is associated with significant risks, including temporary or permanent Horner’s syndrome, persistent neuralgia, and decreased localized cutaneous sweating. An endoscopic approach may be safer. For example, in one study of 28 patients treated using an endoscopic approach, no major complications occurred, and there were no intra- or perioperative deaths .
It is also unclear whether benefits that may occur with sympathectomy persist over time. An epidemiologic survey evaluated 140 patients with RP who had undergone sympathectomy . Only 19 percent claimed lasting benefit, and 66 percent claimed no benefit after one year. However, another series of 25 patients with primary RP and 14 patients with secondary RP demonstrated long-lasting benefits with cervical sympathectomy . The endoscopic technique does not appear to have any advantage over the older open technique in terms of recurrent symptoms, as 82 percent of those who had initial relief of symptoms relapsed [94,97].
Sympathectomy is more likely to be helpful for patients with primary RP; however, these patients rarely need an aggressive surgical approach to therapy. Patients with secondary RP with critical ischemia or active digital ulcers are likely to have some immediate improvement in blood flow following sympathectomy, but the degree and duration of improvement are quite variable. Improvement may last for a relatively short time.
Localized surgical digital sympathectomy — Localized microsurgical digital sympathectomy has been introduced as an alternative to proximal sympathectomy . Although a series of cases has reported successful results and few complications following digital sympathectomy [99-103], its exact role has not been defined by controlled investigations. A review noted that differences in surgical technique, causes of digital ischemia, and outcome measures made comparison of reported series difficult . Amputation and recurrent ulceration following digital sympathectomy were frequent (14 and 18 percent, respectively). Among patients with scleroderma, RP, and digital ischemia, the perioperative complication rate was 37 percent. This procedure should be limited to patients who have failed medical treatment and who continue to have ischemia or severe RP which threatens the involved digit(s). When sympathectomy is decided as a necessary therapeutic option, we advise localized digital sympathectomy over proximal cervical or endoscopic procedures.
We consider surgical sympathectomy only in patients with ischemia or severe RP which threatens viability of the involved digit(s) after vasodilator drugs have failed (see 'Resistant to initial therapies' above) and after specific treatment for any reversible cause, such as vasculitis, has been administered.
Anticoagulation and antithrombotic therapy — Multiple antithrombotic agents have been utilized in patients with RP in whom ulceration and thrombosis have occurred. These include aspirin, dipyridamole, systemic anticoagulation, and thrombolytic therapy.
The benefit of antiplatelet therapy with aspirin (75 or 81 mg/day) is uncertain because of the lack of formal studies, but we suggest the use of low-dose aspirin in all patients with secondary RP who have a history of ischemic ulcers or other thrombotic events. Some clinicians recommend the use of dipyridamole because of its antiplatelet, vasodilating, and antioxidant properties, which may improve vascular tone. However, there is no formal experience with the use of dipyridamole or with the antiplatelet agent clopidogrel for such complex cases of RP with digital ischemia.
We use anticoagulation or thrombolytic therapy during the acute phase of an ischemic event in patients with embolic or vascular occlusive disease associated with new thrombosis :
●Anticoagulation with heparin may be used for short periods during a crisis. Long-term therapy with LMWH in a small placebo-controlled study was associated with a reduction in the severity of RP after 4 and 20 weeks of LMWH ; further study of this approach is needed. However, patients with antiphospholipid antibodies with digital ischemia and RP may benefit from chronic anticoagulation. (See "Treatment of the antiphospholipid syndrome".)
●Thrombolytic therapy (eg, with tissue plasminogen activator) may be helpful in selected patients with RP and scleroderma . Early intervention in patients with a newly defined thrombotic or embolic event is required for it to be effective, and further trials will need to be performed to determine whether this approach will reverse acute ischemia in severe RP [78,79].
Vascular reconstruction — Careful examination for larger vessel disease is recommended because occlusion of a major artery can occur in patients with secondary RP. Microsurgical revascularization of the hand and digital arterial reconstruction may improve digital vascular perfusion and may heal digital ulcers when proximal arterial occlusion is associated with digital vasospasm. As an example, in patients with scleroderma, arterial occlusion most commonly occurs in the ulnar artery and in the proper digital arteries. Revascularization of ulnar artery occlusive disease in this setting may improve RP and may improve healing of digital ulcers .
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient information: Raynaud disease (The Basics)")
●Beyond the Basics topics (see "Patient information: Raynaud phenomenon (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●In patients who do not respond adequately to a calcium channel blocker (CCB) alone, we suggest the addition of a phosphodiesterase (PDE) inhibitor (eg, sildenafil) rather than another orally administered vasodilator or topical nitrate (Grade 2B). Sildenafil is begun at 20 mg once or twice daily, while continuing the CCB if the latter agent has provided some benefit and is tolerated. (See 'Combination of a CCB with other vasodilators' above and 'Phosphodiesterase type 5 inhibitors' above.)
●In patients with an inadequate response to a CCB and for whom a PDE inhibitor is not available, effective, or well-tolerated, we suggest the addition of topical nitroglycerin (NTG) (Grade 2B). Topical NTG (eg, 0.5 inches of 2 percent ointment, approximately 15 mg/inch) should be applied initially to a single more severely affected or ischemic digit for 6 to 12 hours while continuing use of the CCB. (See 'Topical nitrates' above.)
●In patients who do not reach the therapeutic goal or who are unable to tolerate a CCB, a PDE inhibitor, or a topical nitrate, either alone or in combination, alternative agents for which there is some limited evidence of benefit include losartan, prazosin, and fluoxetine. (See 'Other alternatives to CCBs' above.)
●In patients who receive optimal vasodilator therapy with first-line agents but who either have severe symptoms that have a markedly adverse effect upon quality of life or have digital ulcers or macrovascular events associated with Raynaud phenomenon (RP) that threaten digital loss, we suggest treatment with intravenous (IV) infusions of a prostaglandin (PG) (Grade 2A). We prefer to use a prostacyclin (PGI2) analogue (eg, iloprost, epoprostenol, or treprostinil) depending upon availability. (See 'Severe symptoms despite oral and topical agents' above and 'Efficacy of parenteral prostaglandins and analogues' above.)
●We suggest antiplatelet therapy with low-dose aspirin (75 or 81 mg/day) in all patients with secondary RP who have a history of ischemic ulcers or other thrombotic events (Grade 2C). Dipyridamole or clopidogrel are alternative agents that may be used in this setting. We use anticoagulation or thrombolytic therapy during the acute phase of an ischemic event in patients with embolic or vascular occlusive disease associated with new thrombosis. (See 'Anticoagulation and antithrombotic therapy' above.)
●In patients with recurrent digital ulcers associated with scleroderma or related disorders and with continued or recurrent symptoms despite use of other therapies, including CCBs plus other agents and intravenous prostanoids, we suggest the use of bosentan, an orally administered endothelin-1 inhibitor, as the next step rather than other oral agents or sympathectomy (Grade 2B). (See 'Recurrent digital ulcers in scleroderma' above.)
●Patients with a demarcated ischemic digit secondary to larger vessel compromise should be hospitalized, kept warm and quiet, provided adequate analgesia, and evaluated for a secondary reversible process that is causing or aggravating the crisis. Medical therapy with a CCB should be initiated in patients not receiving medical therapy. In patients with scleroderma and acute digital ischemia, if there is no contraindication, we suggest antiplatelet therapy with low-dose aspirin (75 to 81 mg/day) as a component of the initial treatment program (Grade 2C). (See 'Digital ulceration with critical ischemia' above and 'Approach to treatment' above.)
●In patients with digital ulceration with critical ischemia, when oral and/or topical vasodilatory therapy does not quickly result in improvement in digital blood flow and when IV PG are not readily available, we suggest that temporary chemical sympathectomy be performed using a digital or regional (wrist) block with local infiltration of lidocaine or bupivacaine (without epinephrine) (Grade 2C). Patients may also undergo either proximal or distal surgical sympathectomy. (See 'Chemical sympathectomy' above and 'Cervical sympathectomy' above and 'Localized surgical digital sympathectomy' above.)
- Roustit M, Blaise S, Allanore Y, et al. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and meta-analysis of randomised trials. Ann Rheum Dis 2013; 72:1696.
- Thompson AE, Shea B, Welch V, et al. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum 2001; 44:1841.
- Khanna PP, Maranian P, Gregory J, Khanna D. The minimally important difference and patient acceptable symptom state for the Raynaud's condition score in patients with Raynaud's phenomenon in a large randomised controlled clinical trial. Ann Rheum Dis 2010; 69:588.
- Tucker AT, Pearson RM, Cooke ED, Benjamin N. Effect of nitric-oxide-generating system on microcirculatory blood flow in skin of patients with severe Raynaud's syndrome: a randomised trial. Lancet 1999; 354:1670.
- Chung L, Shapiro L, Fiorentino D, et al. MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: a randomized, controlled trial. Arthritis Rheum 2009; 60:870.
- Kan C, Akimoto S, Abe M, et al. Preliminary thermographic evaluation of new nitroglycerine tape on the peripheral circulatory disturbance in systemic sclerosis. Ann Rheum Dis 2002; 61:177.
- Teh LS, Manning J, Moore T, et al. Sustained-release transdermal glyceryl trinitrate patches as a treatment for primary and secondary Raynaud's phenomenon. Br J Rheumatol 1995; 34:636.
- Herrick AL. Contemporary management of Raynaud's phenomenon and digital ischaemic complications. Curr Opin Rheumatol 2011; 23:555.
- Henness S, Wigley FM. Current drug therapy for scleroderma and secondary Raynaud's phenomenon: evidence-based review. Curr Opin Rheumatol 2007; 19:611.
- Vinjar B, Stewart M. Oral vasodilators for primary Raynaud's phenomenon. Cochrane Database Syst Rev 2008; :CD006687.
- Huisstede BM, Hoogvliet P, Paulis WD, et al. Effectiveness of interventions for secondary Raynaud's phenomenon: a systematic review. Arch Phys Med Rehabil 2011; 92:1166.
- Stewart M, Morling JR. Oral vasodilators for primary Raynaud's phenomenon. Cochrane Database Syst Rev 2012; 7:CD006687.
- Russell IJ, Lessard JA. Prazosin treatment of Raynaud's phenomenon: a double blind single crossover study. J Rheumatol 1985; 12:94.
- Wollersheim H, Thien T, Fennis J, et al. Double-blind, placebo-controlled study of prazosin in Raynaud's phenomenon. Clin Pharmacol Ther 1986; 40:219.
- LeRoy EC, Downey JA, Cannon PJ. Skin capillary blood flow in scleroderma. J Clin Invest 1971; 50:930.
- Robson P, Pearce V, Antcliff AC, Hamilton M. Double-blind trial of indoramin in digital artery disease. Br J Clin Pharmacol 1978; 6:88.
- Varadi DP, Lawrence AM. Suppression of Raynaud's phenomenon by methyldopa. Arch Intern Med 1969; 124:13.
- Russell IJ, Walsh RA. Selection of vasodilator therapy for severe Raynaud's phenomenon by sequential arterial infusion. Ann Rheum Dis 1985; 44:151.
- Coffman JD, Cohen RA. Intra-arterial vasodilator agents to reverse human finger vasoconstriction. Clin Pharmacol Ther 1987; 41:574.
- Willerson JT, Thompson RH, Hookman P, et al. Reserpine in Raynaud's disease and phenomenon. Short-term response to intra-arterial injection. Ann Intern Med 1970; 72:17.
- McFadyen IJ, Housley E, MacPherson AI. Intraarterial reserpine administration in Raynaud syndrome. Arch Intern Med 1973; 132:526.
- PRANDONI AG, MOSER M. Clinical appraisal of intra-arterial priscoline therapy in the management of peripheral arterial diseases. Circulation 1954; 9:73.
- Wise RA, Wigley FM, White B, et al. Efficacy and tolerability of a selective alpha(2C)-adrenergic receptor blocker in recovery from cold-induced vasospasm in scleroderma patients: a single-center, double-blind, placebo-controlled, randomized crossover study. Arthritis Rheum 2004; 50:3994.
- Jaffe IA. Serotonin reuptake inhibitors in Raynaud's phenomenon. Lancet 1995; 345:1378.
- Coleiro B, Marshall SE, Denton CP, et al. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford) 2001; 40:1038.
- Dziadzio M, Denton CP, Smith R, et al. Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 1999; 42:2646.
- Gliddon AE, Doré CJ, Black CM, et al. Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 2007; 56:3837.
- Tosi S, Marchesoni A, Messina K, et al. Treatment of Raynaud's phenomenon with captopril. Drugs Exp Clin Res 1987; 13:37.
- Neirotti M, Longo F, Molaschi M, et al. Functional vascular disorders: treatment with pentoxifylline. Angiology 1987; 38:575.
- Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud's phenomenon and digital ulcers. J Rheumatol 2008; 35:1801.
- Kuwana M, Okazaki Y, Kaburaki J. Long-term beneficial effects of statins on vascular manifestations in patients with systemic sclerosis. Mod Rheumatol 2009; 19:530.
- Kuwana M. Potential benefit of statins for vascular disease in systemic sclerosis. Curr Opin Rheumatol 2006; 18:594.
- Mariani E, Mangialasche F, Feliziani FT, et al. Effects of zinc supplementation on antioxidant enzyme activities in healthy old subjects. Exp Gerontol 2008; 43:445.
- Al-Sheikh YA, Ghneim HK. 'The effect of micronutrients on superoxide dismutase in senescent fibroblasts'. Cell Biochem Funct 2011; 29:384.
- Eby GA, Halcomb WW. High-dose zinc to terminate angina pectoris: a review and hypothesis for action by ICAM inhibition. Med Hypotheses 2006; 66:169.
- Sambo P, Amico D, Giacomelli R, et al. Intravenous N-acetylcysteine for treatment of Raynaud's phenomenon secondary to systemic sclerosis: a pilot study. J Rheumatol 2001; 28:2257.
- Rosato E, Borghese F, Pisarri S, Salsano F. The treatment with N-acetylcysteine of Raynaud's phenomenon and ischemic ulcers therapy in sclerodermic patients: a prospective observational study of 50 patients. Clin Rheumatol 2009; 28:1379.
- Denton CP, Bunce TD, Dorado MB, et al. Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud's phenomenon. Rheumatology (Oxford) 1999; 38:309.
- Muir AH, Robb R, McLaren M, et al. The use of Ginkgo biloba in Raynaud's disease: a double-blind placebo-controlled trial. Vasc Med 2002; 7:265.
- Bredie SJ, Jong MC. No significant effect of ginkgo biloba special extract EGb 761 in the treatment of primary Raynaud phenomenon: a randomized controlled trial. J Cardiovasc Pharmacol 2012; 59:215.
- Coffman JD, Clement DL, Creager MA, et al. International study of ketanserin in Raynaud's phenomenon. Am J Med 1989; 87:264.
- Khan F, Litchfield SJ, McLaren M, et al. Oral L-arginine supplementation and cutaneous vascular responses in patients with primary Raynaud's phenomenon. Arthritis Rheum 1997; 40:352.
- Bunker CB, Reavley C, O'Shaughnessy DJ, Dowd PM. Calcitonin gene-related peptide in treatment of severe peripheral vascular insufficiency in Raynaud's phenomenon. Lancet 1993; 342:80.
- Ettinger WH, Wise RA, Schaffhauser D, Wigley FM. Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynaud's phenomenon. Am J Med 1984; 77:451.
- Bowling JC, Dowd PM. Raynaud's disease. Lancet 2003; 361:2078.
- Kumagai S, Morinobu A, Ozaki S, et al. [Sarpogrelate hydrochloride for Raynaud's phenomenon of patients with collagen diseases]. Ryumachi 1998; 38:504.
- Kato S, Kishiro I, Ohnuma N, et al. Suppressive effect of saprogrelate hydrochloride on Raynaud's phenomenon and respiratory failure in patients with systemic sclerosis. Respirology 2000; 5:27.
- Yoshimasu T, Ikeda T, Uede K, et al. Effects of sarpogrelate hydrochloride on skin ulcers and quality of life in patients with systemic sclerosis. J Dermatol 2012; 39:536.
- Pope J, Fenlon D, Thompson A, et al. Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2000; :CD000953.
- Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med 1994; 120:199.
- Dowd PM, Martin MF, Cooke ED, et al. Treatment of Raynaud's phenomenon by intravenous infusion of prostacyclin (PGI2). Br J Dermatol 1982; 106:81.
- Belch JJ, Newman P, Drury JK, et al. Intermittent epoprostenol (prostacyclin) infusion in patients with Raynaud's syndrome. A double-blind controlled trial. Lancet 1983; 1:313.
- Chung L, Fiorentino D. A pilot trial of treprostinil for the treatment and prevention of digital ulcers in patients with systemic sclerosis. J Am Acad Dermatol 2006; 54:880.
- Clifford PC, Martin MF, Sheddon EJ, et al. Treatment of vasospastic disease with prostaglandin E1. Br Med J 1980; 281:1031.
- Mohrland JS, Porter JM, Smith EA, et al. A multiclinic, placebo-controlled, double-blind study of prostaglandin E1 in Raynaud's syndrome. Ann Rheum Dis 1985; 44:754.
- Gardinali M, Pozzi MR, Bernareggi M, et al. Treatment of Raynaud's phenomenon with intravenous prostaglandin E1alpha-cyclodextrin improves endothelial cell injury in systemic sclerosis. J Rheumatol 2001; 28:786.
- Rademaker M, Cooke ED, Almond NE, et al. Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study. BMJ 1989; 298:561.
- Kyle MV, Belcher G, Hazleman BL. Placebo controlled study showing therapeutic benefit of iloprost in the treatment of Raynaud's phenomenon. J Rheumatol 1992; 19:1403.
- Langevitz P, Buskila D, Lee P, Urowitz MB. Treatment of refractory ischemic skin ulcers in patients with Raynaud's phenomenon with PGE1 infusions. J Rheumatol 1989; 16:1433.
- Bettoni L, Geri A, Airò P, et al. Systemic sclerosis therapy with iloprost: a prospective observational study of 30 patients treated for a median of 3 years. Clin Rheumatol 2002; 21:244.
- Pakozdi A, Howell K, Wilson H, et al. Inhaled iloprost for the treatment of Raynaud's phenomenon. Clin Exp Rheumatol 2008; 26:709.
- Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132:425.
- Engel G, Rockson SG. Treprostinil for the treatment of severe digital necrosis in systemic sclerosis. Vasc Med 2005; 10:29.
- Wise RA, Wigley F. Acute effects of misoprostol on digital circulation in patients with Raynaud's phenomenon. J Rheumatol 1994; 21:80.
- Tsukamoto H, Nagasawa K. Successful treatment of Raynaud's phenomenon with limaprost, an oral prostaglandin E1 analogue. Br J Rheumatol 1991; 30:317.
- Lau CS, Belch JJ, Madhok R, et al. A randomised, double-blind study of cicaprost, an oral prostacyclin analogue, in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. Clin Exp Rheumatol 1993; 11:35.
- Vayssairat M. Controlled multicenter double blind trial of an oral analog of prostacyclin in the treatment of primary Raynaud's phenomenon. French Microcirculation Society Multicentre Group for the Study of Vascular Acrosyndromes. J Rheumatol 1996; 23:1917.
- Vayssairat M. Preventive effect of an oral prostacyclin analog, beraprost sodium, on digital necrosis in systemic sclerosis. French Microcirculation Society Multicenter Group for the Study of Vascular Acrosyndromes. J Rheumatol 1999; 26:2173.
- Belch JJ, Capell HA, Cooke ED, et al. Oral iloprost as a treatment for Raynaud's syndrome: a double blind multicentre placebo controlled study. Ann Rheum Dis 1995; 54:197.
- Wigley FM, Korn JH, Csuka ME, et al. Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Arthritis Rheum 1998; 41:670.
- Seibold JR, Wigley FM, Schiopu E, et al. Digital ischemic ulcers in scleroderma treated with oral treprostinil diethanolamine: A randomized, double-blind, placebo-controlled, multicenter study. Arthritis Rheum 2011; 63:S968.
- Iorio ML, Masden DL, Higgins JP. Botulinum toxin A treatment of Raynaud's phenomenon: a review. Semin Arthritis Rheum 2012; 41:599.
- Neumeister MW. The role of botulinum toxin in vasospastic disorders of the hand. Hand Clin 2015; 31:23.
- Zhang X, Hu Y, Nie Z, et al. Treatment of Raynaud's phenomenon with botulinum toxin type A. Neurol Sci 2015; 36:1225.
- Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346:896.
- Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004; 50:3985.
- Matucci-Cerinic M, Denton CP, Furst DE, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2011; 70:32.
- Bridges AJ, Spadone DP. Tissue plasminogen activator treatment of digital thrombosis in severe Raynaud's phenomenon--a case report. Angiology 1993; 44:566.
- Lakshminarayanan S, Vázquez-Abad D, Maestrello SJ, Waterman JR. Treatment of severe Raynaud's phenomenon and ischemic ulcerations with tissue plasimogen activator. Clin Exp Rheumatol 1999; 17:260.
- Wigley FM. Clinical practice. Raynaud's Phenomenon. N Engl J Med 2002; 347:1001.
- Engelhart M. The effect of sympathetic blockade and cooling in Raynaud's phenomenon. Clin Physiol 1990; 10:131.
- Setacci C, de Donato G, Teraa M, et al. Chapter IV: Treatment of critical limb ischaemia. Eur J Vasc Endovasc Surg 2011; 42 Suppl 2:S43.
- Greengrass RA, Feinglass NG, Murray PM, Trigg SD. Continuous regional anesthesia before surgical peripheral sympathectomy in a patient with severe digital necrosis associated with Raynaud's phenomenon and scleroderma. Reg Anesth Pain Med 2003; 28:354.
- Sycha T, Graninger M, Auff E, Schnider P. Botulinum toxin in the treatment of Raynaud's phenomenon: a pilot study. Eur J Clin Invest 2004; 34:312.
- Van Beek AL, Lim PK, Gear AJ, Pritzker MR. Management of vasospastic disorders with botulinum toxin A. Plast Reconstr Surg 2007; 119:217.
- Neumeister MW, Chambers CB, Herron MS, et al. Botox therapy for ischemic digits. Plast Reconstr Surg 2009; 124:191.
- Neumeister MW. Botulinum toxin type A in the treatment of Raynaud's phenomenon. J Hand Surg Am 2010; 35:2085.
- Fregene A, Ditmars D, Siddiqui A. Botulinum toxin type A: a treatment option for digital ischemia in patients with Raynaud's phenomenon. J Hand Surg Am 2009; 34:446.
- Jenkins SN, Neyman KM, Veledar E, Chen SC. A pilot study evaluating the efficacy of botulinum toxin A in the treatment of Raynaud phenomenon. J Am Acad Dermatol 2013; 69:834.
- GIFFORD RW Jr, HINES EA Jr, CRAIG WM. Sympathectomy for Raynaud's phenomenon; follow-up study of 70 women with Raynaud's disease and 54 women with secondary Raynaud's phenomenon. Circulation 1958; 17:5.
- JOHNSTON EN, SUMMERLY R, BIRNSTINGL M. PROGNOSIS IN RAYNAUD'S PHENOMENON AFTER SYMPATHECTOMY. Br Med J 1965; 1:962.
- DE TAKATS G, FOWLER EF. Raynaud's phenomenon. JAMA 1962; 179:1.
- Montorsi W, Ghiringhelli C, Annoni F. Indications and results of the surgical treatment in Raynaud's phenomenon. J Cardiovasc Surg (Torino) 1980; 21:203.
- Matsumoto Y, Ueyama T, Endo M, et al. Endoscopic thoracic sympathicotomy for Raynaud's phenomenon. J Vasc Surg 2002; 36:57.
- de Trafford JC, Lafferty K, Potter CE, et al. An epidemiological survey of Raynaud's phenomenon. Eur J Vasc Surg 1988; 2:167.
- van de Wal HJ, Skotnicki SH, Wijn PF, Lacquet LK. Thoracic sympathectomy as a therapy for upper extremity ischemia. A long-term follow-up study. Thorac Cardiovasc Surg 1985; 33:181.
- Thune TH, Ladegaard L, Licht PB. Thoracoscopic sympathectomy for Raynaud's phenomenon--a long term follow-up study. Eur J Vasc Endovasc Surg 2006; 32:198.
- Flatt AE. Digital artery sympathectomy. J Hand Surg Am 1980; 5:550.
- Egloff DV, Mifsud RP, Verdan C. Superselective digital sympathectomy in Raynaud's phenomenon. Hand 1983; 15:110.
- Wilgis EF. Evaluation and treatment of chronic digital ischemia. Ann Surg 1981; 193:693.
- Drake DB, Kesler RW, Morgan RF. Digital sympathectomy for refractory Raynaud's phenomenon in an adolescent. J Rheumatol 1992; 19:1286.
- Yee AM, Hotchkiss RN, Paget SA. Adventitial stripping: a digit saving procedure in refractory Raynaud's phenomenon. J Rheumatol 1998; 25:269.
- Tomaino MM, Goitz RJ, Medsger TA. Surgery for ischemic pain and Raynaud's' phenomenon in scleroderma: a description of treatment protocol and evaluation of results. Microsurgery 2001; 21:75.
- Wasserman A, Brahn E. Systemic sclerosis: bilateral improvement of Raynaud's phenomenon with unilateral digital sympathectomy. Semin Arthritis Rheum 2010; 40:137.
- Clagett GP, Sobel M, Jackson MR, et al. Antithrombotic therapy in peripheral arterial occlusive disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:609S.
- Denton CP, Howell K, Stratton RJ, Black CM. Long-term low molecular weight heparin therapy for severe Raynaud's phenomenon: a pilot study. Clin Exp Rheumatol 2000; 18:499.
- Hart DA, Fritzler MJ. Regulation of plasminogen activators and their inhibitors in rheumatic diseases: new understanding and the potential for new directions. J Rheumatol 1989; 16:1184.
- Taylor MH, McFadden JA, Bolster MB, Silver RM. Ulnar artery involvement in systemic sclerosis (scleroderma). J Rheumatol 2002; 29:102.